Chemokines and their receptors control the emigration of leukocytes during inflammation. The role of the RANTES (regulated on activation normal T-cell expressed and secreted) receptors CCR1 and CCR5 in the selective recruitment of monocytes, T(H)1-like T-cell clones, and peripheral T cells enriched for CD45RO(+) "memory" cells were tested in a system in which arrest under flow conditions is triggered by RANTES immobilized to activated endothelium. With the use of selective nonpeptide receptor antagonists or blocking antibodies, it was found that the RANTES-induced arrest of these cells was mediated predominantly by CCR1. In contrast, CCR5 mainly contributed to the spreading in shear flow, and both CCR1 and CCR5 supported transendothelial chemotaxis toward RANTES. The data in this study reveal specialized roles of apparently redundant receptors in distinct steps of leukocyte trafficking and suggest that not all receptors currently used to define mononuclear cell subsets are involved in their direct recruitment from the circulation.
Glutamic acid decarboxylase (GAD) has been defined as a major target antigen in insulin-dependent diabetes mellitus (IDDM). To identify the molecular ligands triggering a T cell response to GAD, a panel of human GAD65-specific T lymphocyte lines was generated from peripheral blood of three recent onset IDDM patients. All lines derived from a patient expressing the high-risk-conferring HLA-DR*0301/ *0401 haplotypes recognized a single epitope localized between amino acid positions 270 and 283 of GAD65, a stretch that is located in close proximity to the homology region shared with Coxsackie virus P2-C protein. All lines with this specificity were restricted to the DRA, B1*0401 product of the DR4 haplotype. Analysis of the GAD-specific T cell response in a second patient homozygous for DR4 haplotypes demonstrated that the same DRA, B1*0401 allele selected T cells specific for a different determinant. The T cell response profile in a third patient showed that DR*1501/ *1601-encoding haplotypes could present at least three different epitopes to GAD65-specific T lymphocytes. One of these epitopes was presented by a DR allele associated with the resistance-conferring DRB1*1501 haplotype. GAD-specific T cell lines could not be isolated from HLA class IImatched normal individuals. Our data reveal that ( a ) the T cell response to GAD65 is quite heterogenous in recent onset IDDM patients; ( b ) HLA-DR, not DQ, seems to be the principal restriction element used by T cells present at the onset of the disease; and ( c ) T cells responding to epitopes containing identical sequences to Coxsackie virus P2-C protein were not detected. ( J. Clin. Invest. 1997. 99:2405-2415.)
Many immune responses are controlled by genes of the major histocompatibility complex (MHC). In man these include the loci encoding the HLA-A, -B, -C, -DR, -DQ and -DP antigens, and many diseases have been linked with these. But attempts to identify HLA genes in man that might explain why an immune response against malignant tumours should be ineffective have so far been disappointing, apart from the association reported between the HLA-DR1 antigen and a susceptibility to a rare carcinoma of the thyroid gland. Here we describe another strong connection between a common malignant tumour and an HLA antigen, namely between HLA-DQw3 and squamous cell carcinoma of the cervix: from the 1988 United States tumour registry, 1 in every 63 newborn girls will develop this invasive cancer. We found that 88% of 66 patients had the leukocyte antigen HLA-DQw3 when it would normally be expected in only 50% of individuals. In animals the immune system and the MHC act in defence against virally induced tumours, but until now there has been no evidence that they do so in humans: as squamous cell carcinoma is probably virally induced, our discovery of its association with an HLA antigen will be important to the understanding of the immunogenetic basis of a susceptibility to this tumour.
When human lymphocytes are cultured for 9 to 14 days with stimulating cells of a family member differing by a single HL-A haplotype they become "primed" to recognize specific HL-A LD (mixed lymphocyte culture) antigens. These primed lymphocytes respond specifically and rapidly when "restimulated" with cells of a person that contain the same LD antigens as those of the priming haplotype. Specific HL-A LD antigens can be detected within 24 hours by this primed LD typing.
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